Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies

the Collaborative Group of Italian League Against Epilepsy (LICE) Genetic Commission

Research output: Contribution to journalArticle

Abstract

Objective: We investigated the contribution to sporadic focal epilepsies (FE) of ultrarare variants in genes coding for the components of complexes regulating mechanistic Target Of Rapamycin (mTOR)complex 1 (mTORC1). Methods: We collected genetic data of 121 Italian isolated FE cases and 512 controls by Whole Exome Sequencing (WES) and single-molecule Molecular Inversion Probes (smMIPs) targeting 10 genes of the GATOR1, GATOR2, and TSC complexes. We collapsed “qualifying” variants (ultrarare and predicted to be deleterious or loss of function) across the examined genes and sought to identify their enrichment in cases compared to controls. Results: We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in FE patients (P = 0.006; exact unconditional test, one-tailed). Pathogenic variants were identified in DEPDC5 and TSC2, both major genes for Mendelian FE syndromes. Interpretation: Our findings support the contribution of ultrarare variants in genes in the mTOR pathway complexes GATOR and TSC to the risk of sporadic FE and a shared genetic basis between rare and common epilepsies. The identification of a monogenic etiology in isolated cases, most typically encountered in clinical practice, may offer to a broader community of patients the perspective of precision therapies directed by the underlying genetic cause.

Original languageEnglish
Pages (from-to)475-485
Number of pages11
JournalAnnals of Clinical and Translational Neurology
Volume6
Issue number3
DOIs
Publication statusPublished - Mar 1 2019

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Partial Epilepsy
Sirolimus
Genes
Gene Components
Exome
Molecular Probes
Gene Targeting
Epilepsy

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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the Collaborative Group of Italian League Against Epilepsy (LICE) Genetic Commission (2019). Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies. Annals of Clinical and Translational Neurology, 6(3), 475-485. https://doi.org/10.1002/acn3.722

Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies. / the Collaborative Group of Italian League Against Epilepsy (LICE) Genetic Commission.

In: Annals of Clinical and Translational Neurology, Vol. 6, No. 3, 01.03.2019, p. 475-485.

Research output: Contribution to journalArticle

the Collaborative Group of Italian League Against Epilepsy (LICE) Genetic Commission 2019, 'Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies', Annals of Clinical and Translational Neurology, vol. 6, no. 3, pp. 475-485. https://doi.org/10.1002/acn3.722
the Collaborative Group of Italian League Against Epilepsy (LICE) Genetic Commission. Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies. Annals of Clinical and Translational Neurology. 2019 Mar 1;6(3):475-485. https://doi.org/10.1002/acn3.722
the Collaborative Group of Italian League Against Epilepsy (LICE) Genetic Commission. / Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies. In: Annals of Clinical and Translational Neurology. 2019 ; Vol. 6, No. 3. pp. 475-485.
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abstract = "Objective: We investigated the contribution to sporadic focal epilepsies (FE) of ultrarare variants in genes coding for the components of complexes regulating mechanistic Target Of Rapamycin (mTOR)complex 1 (mTORC1). Methods: We collected genetic data of 121 Italian isolated FE cases and 512 controls by Whole Exome Sequencing (WES) and single-molecule Molecular Inversion Probes (smMIPs) targeting 10 genes of the GATOR1, GATOR2, and TSC complexes. We collapsed “qualifying” variants (ultrarare and predicted to be deleterious or loss of function) across the examined genes and sought to identify their enrichment in cases compared to controls. Results: We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in FE patients (P = 0.006; exact unconditional test, one-tailed). Pathogenic variants were identified in DEPDC5 and TSC2, both major genes for Mendelian FE syndromes. Interpretation: Our findings support the contribution of ultrarare variants in genes in the mTOR pathway complexes GATOR and TSC to the risk of sporadic FE and a shared genetic basis between rare and common epilepsies. The identification of a monogenic etiology in isolated cases, most typically encountered in clinical practice, may offer to a broader community of patients the perspective of precision therapies directed by the underlying genetic cause.",
author = "Laura Licchetta and Tommaso Pippucci and Sara Baldassari and Caterina Marconi and {De Luise}, Monica and Candace Myers and Elena Nardi and Federica Provini and Cinzia Cameli and Raffaella Minardi and Elena Bacchelli and Lucio Giordano and Giovanni Crichiutti and Giuseppe d'Orsi and Marco Seri and Giuseppe Gasparre and Mefford, {Heather C.} and Paolo Tinuper and Francesca Bisulli and {the Collaborative Group of Italian League Against Epilepsy (LICE) Genetic Commission} and Amedeo Bianchi and Pasquale Striano and Antonio Gambardella and Stefano Meletti and Roberto Dilena and Margherita Santucci and Carla Marini and Aglaia Vignoli and Giuseppe Gobbi and Eleonora Briatore and Massimo Mastrangelo",
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AU - Pippucci, Tommaso

AU - Baldassari, Sara

AU - Marconi, Caterina

AU - De Luise, Monica

AU - Myers, Candace

AU - Nardi, Elena

AU - Provini, Federica

AU - Cameli, Cinzia

AU - Minardi, Raffaella

AU - Bacchelli, Elena

AU - Giordano, Lucio

AU - Crichiutti, Giovanni

AU - d'Orsi, Giuseppe

AU - Seri, Marco

AU - Gasparre, Giuseppe

AU - Mefford, Heather C.

AU - Tinuper, Paolo

AU - Bisulli, Francesca

AU - the Collaborative Group of Italian League Against Epilepsy (LICE) Genetic Commission

AU - Bianchi, Amedeo

AU - Striano, Pasquale

AU - Gambardella, Antonio

AU - Meletti, Stefano

AU - Dilena, Roberto

AU - Santucci, Margherita

AU - Marini, Carla

AU - Vignoli, Aglaia

AU - Gobbi, Giuseppe

AU - Briatore, Eleonora

AU - Mastrangelo, Massimo

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N2 - Objective: We investigated the contribution to sporadic focal epilepsies (FE) of ultrarare variants in genes coding for the components of complexes regulating mechanistic Target Of Rapamycin (mTOR)complex 1 (mTORC1). Methods: We collected genetic data of 121 Italian isolated FE cases and 512 controls by Whole Exome Sequencing (WES) and single-molecule Molecular Inversion Probes (smMIPs) targeting 10 genes of the GATOR1, GATOR2, and TSC complexes. We collapsed “qualifying” variants (ultrarare and predicted to be deleterious or loss of function) across the examined genes and sought to identify their enrichment in cases compared to controls. Results: We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in FE patients (P = 0.006; exact unconditional test, one-tailed). Pathogenic variants were identified in DEPDC5 and TSC2, both major genes for Mendelian FE syndromes. Interpretation: Our findings support the contribution of ultrarare variants in genes in the mTOR pathway complexes GATOR and TSC to the risk of sporadic FE and a shared genetic basis between rare and common epilepsies. The identification of a monogenic etiology in isolated cases, most typically encountered in clinical practice, may offer to a broader community of patients the perspective of precision therapies directed by the underlying genetic cause.

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